The conformational changes of both partners of a ligand-protein complex, the small-molecule ligand its the protein binding site (in many cases the catalytically active site of an enzyme) are a central aspect many drug actions, as well as a crucial challenge in computational approaches to drug design. In one of the earliest publications in the this field, we <A HREF="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8581425&ordinalpos=47&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum">showed</A> for a small set of ligands occurring both in the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD) that flexible compounds are not usually bound to a protein in their global vacuum energy conformation, and oftentime not even in any local vacuum energy conformation. <BR> While this study used the largest set of data and best methodology available at that time, both the number of structures in either experimental database and the software and hardware resource available have since grown exponentially. <BR> We are thus revisiting this important topic with an analysis of orders of magnitudes more structures, and computations performed at a high level of computational quantum-chemical theory. <BR> Among other milestones achieved so far in this project, we have extracted all occurrences of small-molecule ligands in the PDB with their 3D coordinates, and with extensive annotation added, combined from several different sources. As of August 2007, this is a set of over 106,000 structures. This will allow us to conduct a detailed analysis not only of the conformational changes observed in protein-ligand crystal structures, but also of potential quality issues of these crystal structures themselves.